Targeting dynamic ATP-binding site features allows discrimination between highly homologous protein kinases
| Autor: | Takayuki Inukai, Sujata Chakraborty, Martin Golkowski, Linglan Fang, Dustin J. Maly |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Protein Conformation Protein domain Computational biology Plasma protein binding 01 natural sciences Biochemistry Article 03 medical and health sciences Protein structure Adenosine Triphosphate Protein Domains LYN Kinome Binding site Phosphorylation Protein Kinase Inhibitors Binding Sites 010405 organic chemistry Kinase Chemistry General Medicine Protein superfamily 0104 chemical sciences 030104 developmental biology src-Family Kinases Molecular Medicine Protein Binding |
| Zdroj: | ACS Chem Biol |
| Popis: | ATP-competitive inhibitors that demonstrate exquisite selectivity for specific members of the human kinome have been developed. Despite this success, the identification of highly selective inhibitors is still very challenging, and it is often not possible to rationally engineer selectivity between the ATP-binding sites of kinases, especially amongst closely-related family members. Src-family kinases (SFKs) are a highly homologous family of eight multi-domain, non-receptor tyrosine kinases that play general and specialized roles in numerous cellular processes. The high sequence and functional similarities between SFK members make it hard to rationalize how selectivity can be gained with inhibitors that target the ATP-binding site. Here, we describe the development of a series of inhibitors that are highly selective for the ATP-binding sites of the SFKs Lyn and Hck over other SFKs. By biochemically characterizing how these selective ATP-competitive inhibitors allosterically influence the global conformation of SFKs, we demonstrate that they most likely interact with a binding pocket created by the movement of the conformationally-flexible helix αC in the ATP-binding site. With a series of sequence swap experiments, we show that sensitivity to this class of selective inhibitors is due to the identity of residues that control the conformational flexibility of helix αC rather than any specific ATP-binding site interactions. Thus, the ATP-binding sites of highly homologous kinases can be discriminated by targeting heterogeneity within conformationally flexible regions. |
| Databáze: | OpenAIRE |
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